Mechanisms of the proteinuria induced by Rho GTPases

Liming Wang, Mathew J. Ellis, Jose A. Gomez, William Eisner, Walter Fennell, David N. Howell, Phillip Ruiz, Timothy A. Fields, Robert F. Spurney

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14 Rho) or dominant-negative Rho A (N19 Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin-associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14 Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19 Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.

Original languageEnglish (US)
Pages (from-to)1075-1085
Number of pages11
JournalKidney international
Volume81
Issue number11
DOIs
StatePublished - Jun 1 2012

Keywords

  • cell signaling
  • glomerular disease
  • podocyte

ASJC Scopus subject areas

  • Nephrology

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    Wang, L., Ellis, M. J., Gomez, J. A., Eisner, W., Fennell, W., Howell, D. N., Ruiz, P., Fields, T. A., & Spurney, R. F. (2012). Mechanisms of the proteinuria induced by Rho GTPases. Kidney international, 81(11), 1075-1085. https://doi.org/10.1038/ki.2011.472